TY - JOUR
T1 - Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging
AU - Means, John C.
AU - Gerdes, Bryan C.
AU - Kaja, Simon
AU - Sumien, Nathalie
AU - Payne, Andrew J.
AU - Stark, Danny A.
AU - Borden, Priscilla K.
AU - Price, Jeffrey L.
AU - Koulen, Peter
N1 - Funding Information:
Acknowledgments Research reported in this publication was supported in part by Grants AG022550, AG027956 (NS, PK), AG010485 from NIH/NIA, RR022570 and RR027093 from NIH/NCRR and EY022774 from NIH/NEI (PK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research, the Vision Research Foundation of Kansas City and a departmental challenge grant by Research to Prevent Blindness (PK) is gratefully acknowledged. The authors thank Michael J. Forster, Margaret, Richard and Sara Koulen for generous support and encouragement.
Funding Information:
Research reported in this publication was supported in part by Grants AG022550, AG027956 (NS, PK), AG010485 from NIH/NIA, RR022570 and RR027093 from NIH/NCRR and EY022774 from NIH/NEI (PK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research, the Vision Research Foundation of Kansas City and a departmental challenge grant by Research to Prevent Blindness (PK) is gratefully acknowledged. The authors thank Michael J. Forster, Margaret, Richard and Sara Koulen for generous support and encouragement.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Mouse models of neurodegenerative diseases such as Alzheimer’s disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and with time interrupt cognitive function. Here, we introduce a non-genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates with increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly correlated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain.
AB - Mouse models of neurodegenerative diseases such as Alzheimer’s disease (AD) are important for understanding how pathological signaling cascades change neural circuitry and with time interrupt cognitive function. Here, we introduce a non-genetic preclinical model for aging and show that it exhibits cleaved tau protein, active caspases and neurofibrillary tangles, hallmarks of AD, causing behavioral deficits measuring cognitive impairment. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans with potentially high impact on both new basic research into pathogenic mechanisms and new translational research efforts. Tau aggregation is a hallmark of tauopathies, including AD. Recent studies have indicated that cleavage of tau plays an important role in both tau aggregation and disease. In this study we use wild type mice as a model for normal aging and resulting age-related cognitive impairment. We provide evidence that aged mice have increased levels of activated caspases, which significantly correlates with increased levels of truncated tau and formation of neurofibrillary tangles. In addition, cognitive decline was significantly correlated with increased levels of caspase activity and tau truncated by caspase-3. Experimentally induced inhibition of caspases prevented this proteolytic cleavage of tau and the associated formation of neurofibrillary tangles. Our study shows the strength of using a non-transgenic model to study structure, function and molecular mechanisms in aging and age related diseases of the brain.
KW - Age-related cognitive decline
KW - Molecular mechanisms in brain aging
KW - Neurofibrillary tangles
KW - Preclinical
KW - Tauopathy
UR - http://www.scopus.com/inward/record.url?scp=84970016708&partnerID=8YFLogxK
U2 - 10.1007/s11064-016-1942-9
DO - 10.1007/s11064-016-1942-9
M3 - Article
C2 - 27220334
AN - SCOPUS:84970016708
SN - 0364-3190
VL - 41
SP - 2278
EP - 2288
JO - Neurochemical Research
JF - Neurochemical Research
IS - 9
ER -